title: Preclinical pharmacokinetic/pharmacodynamic/efficacy relationships for alisertib, an investigational small-molecule inhibitor of Aurora A kinase.
abstract: OBJECTIVE
  Alisertib (MLN8237) is an investigational inhibitor of Aurora A kinase (AAK). Aurora A plays an essential role in the regulation of spindle assembly and chromosome alignment during mitosis. Inhibition of Aurora A by alisertib in tissue culture has previously been demonstrated to lead to improper chromosomal alignment and disruption of spindle organization, resulting in a transient mitotic delay. The spindle organization defects induced by alisertib have been used to develop a pharmacodynamic (PD) assay for Aurora A inhibition based on the percentage of mitotic cells with proper chromosomal alignment at the metaphase plate (% aligned spindles, abbreviated as AS). The transient mitotic delay that occurs with AAK inhibition permits the use of the mitotic index (the fraction of cells in the population currently undergoing mitosis, abbreviated as MI) as an additional PD assay. When the two PD assays were used in Phase I clinical trials, the reduction in AS was strongly correlated with dose levels and exposures in patients from single time point PD measurements; however, MI failed to show any correlation. To further understand this clinical finding, we constructed PK/PD/efficacy models for AS and MI that can precisely capture the temporal dynamics of the PD markers from in vivo xenograft studies.
  
  
  METHODS
  A PK/PD study was conducted using a single oral dose of alisertib at 3, 10, and 20 mg/kg in HCT-116 xenografts implanted subcutaneously in mice. An extravascular, two-compartmental pharmacokinetic (PK) model was used to describe the drug kinetics. Consistent with the mechanistic hypothesis for AAK inhibition, the PD biomarkers such as AS and MI were fitted to PK using a direct response inhibitory sigmoid model and an indirect response turnover model, respectively. The antitumor activity of alisertib dosed orally for 21 days with different dose levels and schedules was evaluated.
  
  
  RESULTS
  The PK/PD models showed a fast, sustained response for AS after alisertib administration, whereas MI exhibited a slow, transient response. The PK/efficacy relationship for alisertib in HCT-116 xenografts closely corresponds to the PK/PD relationship for the PD markers, with all three IC50s in close agreement (303, 270, and 280 nM, respectively).
  
  
  CONCLUSIONS
  The PK/PD and PK/efficacy models show that both AS and MI are equally relevant as mechanism-based PD markers to capture drug activity. However, of the two PD markers, the fast, sustained response of AS makes it the only clinically viable PD marker for defining a dose-response relationship, as its maximal effect can be captured from a wider time window with a single PD sampling; while the window to capture dose-related MI response is narrower.
authors.affiliation: Drug Metabolism and Pharmacokinetics, Millennium: The Takeda Oncology Company, Cambridge, MA, 02138, USA, santhosh.palani@gmail.com.
authors.forename: Santhosh
authors.initials: S
authors.lastname: Palani
authors.forename: Mayankbhai
authors.initials: M
authors.lastname: Patel
authors.forename: Jessica
authors.initials: J
authors.lastname: Huck
authors.forename: Mengkun
authors.initials: M
authors.lastname: Zhang
authors.forename: Suresh K
authors.initials: SK
authors.lastname: Balani
authors.forename: Johnny
authors.initials: J
authors.lastname: Yang
authors.forename: Susan
authors.initials: S
authors.lastname: Chen
authors.forename: Jerome
authors.initials: J
authors.lastname: Mettetal
authors.forename: Mark
authors.initials: M
authors.lastname: Manfredi
authors.forename: Wen Chyi
authors.initials: WC
authors.lastname: Shyu
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Ecsedy
authors.forename: Arijit
authors.initials: A
authors.lastname: Chakravarty
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors; D001381:Azepines / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D045325:HCT116 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D011743:Pyrimidines / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001381:Azepines; C550258:MLN 8237; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D064096:Aurora Kinase A